The overall objective of this application is to improve the understanding of early events leading to Barrett's esophagus (a risk factor for esophageal adenocarcinoma) and to identify potential targets for early intervention. Barrett's esophagus is a metaplastic change in the lining of the esophagus that is commonly considered to be a strong risk factor for and precursor to esophageal adenocarcinoma. The incidence of esophageal adenocarcinoma has been rising more rapidly than that of any malignancy in the United States for the last three decades;however, explanations for the marked incidence increase and its marked incidence variation by race and gender (three times more common among Caucasian men than among women or African Americans) remain elusive. Gastroesophageal reflux is a major risk factor for esophageal adenocarcinoma. Obesity is also a major risk factor for many cancers (including esophageal adenocarcinoma), although the mechanisms are unknown and recent research suggests the associations between obesity and cancer are not mediated solely through reflux. Thus, the pathway between obesity and cancer may be through intermediary, adipose- associated hormones, such as leptin, adiponectin, and ghrelin. These hormone systems have known associations with other cancers and demonstrated experimental effects on gastrointestinal inflammation, healing, and the risk of neoplasia. Their levels and even the direction of their effects (adverse vs. protective) may also differ by sex and race. They therefore represent a potential mechanistic link in the individual pathway to Barrett's esophagus and may help explain why, among many persons with reflux disease, only some develop Barrett's esophagus and esophageal adenocarcinoma. They may also partially explain the male/female disparities for this cancer. The specific aims of this study will be to evaluate the associations between leptin, adiponectin, and ghrelin and the risk of Barrett's esophagus, compared with GERD controls and population controls. The project will supplement our current adipokine investigations by adding serum and data from centers in the recently formed NIH/NCI Barrett's esophagus and Esophageal Adenocarcinoma Consortium (BEACON). This will permit an unparalleled opportunity to substantially expand the power and scope of current research to include sex-specific and GERD-specific risk differences for Barrett's esophagus. The consortium consists of five large NIH-funded population/community-based case-control studies with completed patient recruitment. The proposed research will extend a highly novel translational research effort, is supported by a substantial body of literature for similar disorders, will provide a powerful, definitive, multi- center evaluation of the role of adipokines, can leverage resources from an existing productive international multidisciplinary research team, and may permit elucidation of an entirely new direction in determining why only some patients with GERD get Barrett's esophagus and the striking male/female differences in disease risk.